The purpose of this Funding Opportunity Announcement (FOA)
is to invite applications for Centers for Advanced Diagnostics and Experimental
Therapeutics in Lung Diseases Stage II (CADET II). The goal of the CADET
program is to accelerate the development of novel products for the treatment
of lung diseases and sleep disordered breathing using strategies based on
relevant pathobiologic processes. Whereas the prior funding opportunity,
CADET I, provided the opportunity to explore and validate potential
therapeutic targets, the current funding opportunity, CADET II, hereafter
designated "CADET," will support preclinical research on therapeutic
products for which the target has been validated. It is anticipated that
CADET projects may vary substantially in their objectives and scope of
research.

CADET applications must describe research that contributes
to the development of a therapeutic product that modulates a validated target
of clinical significance in lung disease or sleep disordered breathing.
Applications may include concurrent development of a diagnostic test(s)
designed to assess a pathobiologic process associated with the therapeutic
target. Applications must propose two separate groups of activities to be
completed sequentially in the first two years (the UH2 component) and the
final 3 years (the UH3 component) of funding. Although applications for the
UH2 and UH3 activities must be submitted and will be reviewed simultaneously,
funding for the UH3 component is contingent on achieving pre-specified
milestones during the UH2 component. These milestones will ensure sufficient
progress during the UH2 to provide feasibility and scientific rationale for
the conduct of research proposed in the UH3. Milestones must be identified in
the application, and these may be negotiated based on comments of the peer
review panel. Applicants should consult with their institution's legal
authorities to plan for how intellectual property resulting from the research
will be protected.

Key Dates

Posted Date

July 17, 2013

Open Date (Earliest Submission Date)

September 17, 2013

Letter of Intent Due Date(s)

September 17, 2013

Application Due Date(s)

(Extended to November 1, 2013 per NOT-OD-14-003)October 17, 2013, by 5:00 PM local time of applicant
organization.

Applicants are encouraged to apply early to allow adequate
time to make any corrections to errors found in the application during the
submission process by the due date.

It is critical that applicants follow the instructions in
the SF424
(R&R) Application Guide, except where instructed to do otherwise (in
this FOA or in a Notice from the NIH Guide for Grants and Contracts).
Conformance to all requirements (both in the Application Guide and the FOA)
is required and strictly enforced. Applicants must read and follow all
application instructions in the Application Guide as well as any
program-specific instructions noted in Section
IV. When the program-specific instructions deviate from those in the
Application Guide, follow the program-specific instructions. Applications that
do not comply with these instructions may be delayed or not accepted for review.

Advances in understanding of the biology of pulmonary
diseases and sleep disordered breathing have generated enormous potential for
the development of new diagnostic and therapeutic products that can improve
patient care. The purpose of this funding opportunity is to promote the
development of new therapeutic products for the management of lung diseases and
sleep disordered breathing that is based on pathobiologic research. This
funding opportunity will provide support and resources needed to facilitate
preclinical product development, with the intent of enabling improvements in
clinical care based on scientific understanding of disease mechanisms.

Supported Research Activities

CADET will provide grant support for research that is needed
to develop specific products for use in treating diseases of the lung or sleep
disordered breathing. The NHLBI does not support projects primarily focused on
malignancy-related research, vaccine development, or pathogens per se.
Therefore, applicants are strongly encouraged to contact the NHLBI before
submitting an application to determine its appropriateness for this FOA. In
this context, "product" refers to a substance intended to be used for
therapeutic purposes, such as a drug or biologic, but not a device or
test/assay. All proposed studies must lead toward US regulatory approval of a
specific therapeutic product. This program targets that portion of drug
development between target validation and Investigational New Drug (IND)
filing. "Target validation" refers to the identification and
demonstration that a target has a sufficient role in disease biology to impact
a clinically detectable and significant aspect of the disease. Targets may
include but are not limited to specific biologic molecules or a part of a
molecule (e.g., a receptor), a pathway or system, or a biologic process.
Although limited target validation studies may be proposed in CADET, it is
anticipated that competitive applications will involve a precisely defined
target that was previously validated.

Research activities that are often required in the interval
of product development between target validation and IND filing and may be
appropriate for CADET support include the following:

Identify compounds that modulate a validated target and assess
their pre-clinical proof of principle and efficacy.

Evaluate the selectivity, functionality, and
"drugability" of compounds that modulate the target to select a lead
candidate.

Determine the absorption, metabolism, distribution, and
elimination of a lead candidate.

Perform toxicology and bioavailability studies in an animal
model.

Manufacture and scale up production of a lead candidate.

Pre-formulation.

Develop and validate concomitant diagnostic tests.

The use of CADET resources is limited to activities that are
IND enabling. Hence, in addition to describing the specific studies to be
completed with CADET resources, CADET applications must describe an overall
product development plan that will lead to IND filing. The plan should begin
with scientific identification of a pathobiologic process and end with IND
filing. The plan must be summarized using a timeline in the grant application.
The timeline should identify the specific studies proposed for support in
CADET, noting that the cumulative data collected by the conclusion of CADET may
not be sufficient for an IND without additional research. Nevertheless, the
application must include a clear rationale for how the research proposed to be
conducted in CADET will enable IND filing for the therapeutic product. The
UH2/UH3 activity code is used to allow a stepwise progression of the
development of a proposed therapeutic product. Funding of the UH3 component is
contingent upon the successful completion of UH2 aims and specific, agreed upon
activities and milestones, as determined by NHLBI with the recommendations of
the External Advisory Board (EAB) prior to the UH3 award. For example, studies
of absorption, metabolism, distribution, and elimination in the UH3 phase might
be dependent on lead candidate refinement proposed for a UH2. Similarly, UH3
support for scale up production of a lead candidate might be contingent on
animal toxicological studies supported with a UH2 grant. Applicants should
consult with their institution's legal authorities to plan for how intellectual
property resulting from the research will be protected.

CADET applications must focus on the development of a
specific therapeutic product that modulates a particular target. In addition,
applicants may propose concurrent activities needed to develop and validate a
diagnostic test. Herein, "diagnostic test" or "diagnostic"
refers to any assessment that can aid in clinical management. For example, a
diagnostic test could allow selection of a patient population in which the
product is expected to have more efficacious and/or less adverse effects based
on pathobiologic processes. The results of the assessment may be qualitative
(e.g., categories such as high and low) or quantitative with defined units of
measurement. Concurrent development of a diagnostic test is optional for
applications involving novel therapeutics (as defined below) but is required
for any application involving products previously given an IND in the context
of another disease or existing products that do not require an IND (i.e., have
not been used as therapeutic agents such as a vitamin). For previously
developed products, applicants must clearly describe how incorporating the use
of a diagnostic test in conjunction with the product will provide a novel,
biologically-based approach to management. Similar to therapeutic products,
the entire diagnostic development plan does not need to be completed with CADET
support. A summary of the plan for diagnostic development demonstrating an
understanding of the development process, including how it will be used with
the therapeutic product in clinical practice and how any needed regulatory
approval will be obtained, must be included in applications with diagnostics.

CADET Requirements

Applications will be considered responsive to this FOA only
if they include all of the following elements:

1. A product development plan for at least one therapeutic
for use in pulmonary disease or sleep disordered breathing.

2. Proposed studies to develop a therapeutic approach that
is novel and based on modulation of a target that impacts disease biology and,
therefore, clinical outcome(s). To meet this requirement, either A or B and the
associated subtext must be accurate:

A) The therapeutic product itself is novel, meaning it has not
been tested previously.

There
cannot be an existing IND (for any indication).

The
product cannot have been investigated by someone else or used widely.

B) The product requires a new IND because:

The
product will be used for a new indication and in a "target" patient
population defined by disease biology using a diagnostic test. Using an
existing drug for which an IND was previously filed and merely changing the
indication (a different disease or outcome) or combining existing products is
not sufficiently "novel" to be considered responsive to this FOA.

3. Planned research activities that progress beyond target
validation and will enable an IND application.

4. Proposed milestones (for both the UH2 and UH3 segments of
the grant period) that can be used to assess accomplishments and progress
toward IND submission.

Applications will be considered non-responsive to this FOA
if any of the following are included in the application:

1. Studies of combination products that include only
elements of previously approved products (e.g., combining an approved drug with
a device to deliver it as an aerosol).

2. Studies for changing the indication (disease) for an
approved product without a novel approach to management (e.g., using a drug
approved for use in COPD patients in patients with asthma).

3. Using an existing product in a sub-population of patients
that is identified by an existing test (e.g., using Vitamin D in subjects who
are Vitamin D deficient).

4. Clinical trials.

Organization and Operations of the CADET Program

Development of therapeutics and diagnostics requires an
especially dynamic approach to research because intermediate results may
substantially alter the feasibility of subsequent studies or the relative value
of alternative study designs. Therefore the CADET program is intended to allow
grantees to adapt their research plans as appropriate during the project period
with NHLBI oversight.

1. Grants will be awarded as Cooperative Agreements, with
Terms and Conditions of Award that involve program staff of the NHLBI in the
ongoing monitoring and evaluation of research activities. This arrangement will
provide timely review and communication of decisions regarding modifications to
research plans that are indicated by information that becomes available after
the funding period begins.

2. Grants will be structured in two phases - an initial UH2
grant and a subsequent UH3 grant whose funding will be contingent on the
completion of UH2 aims as determined by pre-negotiated milestones. Separation
of the proposed studies into two phases is intended to encourage highly
innovative and potentially high risk research. Applications must propose two
separate groups of activities to be completed sequentially in the first two
years (the UH2 component) and the final three years (the UH3 component) of
funding.

3. NHLBI will form an External Advisory Board (EAB),
including members with expertise in United States Regulations, manufacturing,
toxicology, and pharmacology, to assist NHLBI staff in overall monitoring of
project performance, interim data evaluation, and requests for changes in
research plans. Prior to initiating the individual projects,the EAB will make
recommendations to NHLBI regarding the specific research plans and associated
milestones for those projects selected for funding. The EAB will also review
periodic progress reports and advise the NHLBI regarding the completion of
milestonesand
is expected to convene via regular teleconferences and up to 4 in person
meetings per year in Bethesda, MD.

4. Upon request, NHLBI staff will assist CADET grantees to
apply for the use of services that are provided by the following NHLBI resource
organizations: Science Moving towArds Research Translation and Therapy (SMARTT)
Program, NHLBI's Production Assistance for Cellular Therapies (PACT) Program,
and NHLBI's Gene Therapy Resource Program (GTRP). These NHLBI resource programs
have the capacity to provide the services that are necessary for preclinical
drug development and may not be available at an applicant's own institution.
CADET applicants are strongly encouraged to propose using these services as
appropriate for their therapeutic development plans with the following
restrictions:

Investigators must conduct at least 40% of the research in the
therapeutic development plan at their own institution(s). This means that 40%
of the direct costs over the funding period must be used for research at the
investigators' institution(s).

For any research planned to be conducted outside of the
investigators' institution(s), including research that may be done through the
NHLBI research programs, an estimated cost for the work must be included in the
budget.

For
services performed by non-NHLBI research programs, subcontracts may be
proposed.

CADET
will not award costs for services provided in-kind through SMARTT, PACT, or
GTRP.

Section II. Award Information

Funding Instrument

Cooperative Agreement: A support mechanism used when there
will be substantial Federal scientific or programmatic involvement.
Substantial involvement means that, after award, NIH scientific or program
staff will assist, guide, coordinate, or participate in project activities.

Application Types Allowed

New

The OER
Glossary and the SF424 (R&R) Application Guide provide details on
these application types.

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations
and the submission of a sufficient number of meritorious applications.

NHLBI intends to fund up to 10 awards, corresponding
to a total of $75,000,000 for fiscal years 2014-2018.

Award Budget

Direct costs for a single application may be up to
$1,000,000 annually.

Award Project Period

For UH2/UH3 applications the maximum project period is five
years (two years for the UH2 portion and three years for the UH3 portion).
Funded grants will receive UH3 funding contingent on successful completion of
pre-negotiated milestones for the UH2 period.

NIH grants policies as
described in the NIH Grants
Policy Statement will apply to the
applications submitted and awards made in response to this FOA.

Section III. Eligibility
Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

Public/State Controlled Institutions of Higher Education

Private Institutions of Higher Education

The following types of Higher Education Institutions
are always encouraged to apply for NIH support as Public or Private
Institutions of Higher Education:

Applicant organizations must complete and maintain the
following registrations as described in the SF 424 (R&R) Application Guide
to be eligible to apply for or receive an award. All registrations must be
completed prior to the application being submitted. Registration can take 6
weeks or more, so applicants should begin the registration process as soon as
possible. The NIH
Policy on Late Submission of Grant Applications states that failure to
complete registrations in advance of a due date is not a valid reason for a
late submission.

Dun and Bradstreet Universal
Numbering System (DUNS) - All registrations require that applicants be
issued a DUNS number. After obtaining a DUNS number, applicants can begin both
SAM and eRA Commons registrations. The same DUNS number must be used for all
registrations, as well as on the grant application.

System for Award Management (SAM) (formerly CCR) – Applicants must complete and maintain an active registration, which requires renewal at least
annually. The renewal process may require as much time as the
initial registration. SAM registration includes the assignment of a Commercial
and Government Entity (CAGE) Code for domestic organizations which have not
already been assigned a CAGE Code.

eRA Commons - Applicants
must have an active DUNS number and SAM registration in order to complete the
eRA Commons registration. Organizations can register with the eRA Commons as
they are working through their SAM or Grants.gov registration. eRA Commons
requires organizations to identify at least one Signing Official (SO) and at
least one Program Director/Principal Investigator (PD/PI) account in order to
submit an application.

Grants.gov – Applicants must
have an active DUNS number and SAM registration in order to complete the
Grants.gov registration.

Program
Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account and should
work with their organizational officials to either create a new account or to
affiliate an existing account with the applicant organization’s eRA Commons
account. If the PD/PI is also the organizational Signing Official, they must
have two distinct eRA Commons accounts, one for each role. Obtaining an eRA
Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal
Investigator)

Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director(s)/Principal
Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH support.

Applicant organizations may submit more than one application,
provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the
same as one already reviewed within the past thirty-seven months (as described
in the NIH
Grants Policy Statement), except for submission:

To an RFA of an application that was submitted previously as an
investigator-initiated application but not paid;

Of an investigator-initiated application that was originally
submitted to an RFA but not paid; or

Of an application with a changed grant activity code.

It is anticipated that applicants will benefit from
consultation with experts in therapeutic development and may require external
collaborators to complete the research needed for their project. Funded
projects (and budgets) will be reviewed by the EAB with an assessment of the
necessary pre-clinical studies. Final research plans at the time of award must
include at least 40% of the research (based on direct cost budget) conducted at
the investigators' institution(s).

Section IV. Application and Submission Information

1. Requesting an
Application Package

Applicants must download the SF424 (R&R) application
package associated with this funding opportunity using the “Apply for Grant
Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in
the SF424
(R&R) Application Guide, except where instructed in this funding
opportunity announcement to do otherwise. Conformance to the requirements in
the Application Guide is required and strictly enforced. Applications that are
out of compliance with these instructions may be delayed or not accepted for
review.

Although a letter of intent is not required, is not binding,
and does not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review workload and
plan the review.

By the date listed in Part 1. Overview
Information, prospective applicants are asked to submit a letter of intent
that includes the following information:

All page limitations described in the SF424 Application
Guide and the Table of
Page Limits must be followed.

Required and Optional Components

The forms package associated with this FOA includes all
applicable components, required and optional. Please note that some components
marked optional in the application package are required for submission of
applications for this FOA. Follow all instructions in the SF424 (R&R)
Application Guide to ensure you complete all appropriate “optional” components.

Instructions for Application Submission

The following section supplements the instructions found in
the SF424 (R&R) Application Guide and should be used for preparing an
application to this FOA.

SF424(R&R) Cover

All instructions in the SF424 (R&R) Application Guide
must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the SF424 (R&R) Application Guide
must be followed.

SF424(R&R) Other Project Information

All instructions in the SF424 (R&R) Application Guide
must be followed.

SF424(R&R) Senior/Key Person Profile

All instructions in the SF424 (R&R) Application Guide
must be followed.

R&R Budget

All instructions in the SF424 (R&R) Application Guide
must be followed.

The total direct cost for each application cannot exceed $1
million dollars annually, exclusive of the Facilities and Administrative costs
of first tier subcontracts. This must include the costs for all research
conducted, including work performed at an organization other than the PD/PI
institution.

PHS 398 Cover Page Supplement

All instructions in the SF424 (R&R) Application Guide
must be followed.

PHS 398 Research Plan

All instructions in the SF424 (R&R) Application Guide
must be followed, with the following additional instructions:

Research
Strategy:

The research strategy should include the following three
CADET requirements:

1. Product development plan

a. Must begin with scientific identification of a
pathobiologic process and end with IND filing.

b. Must be summarized using a timeline that specifies
which of the studies are proposed for support in CADET.

2. Proposed milestones (for both the UH2 and UH3 segments of
the grant period).

3. An explicit statement of the IND status of the proposed
therapeutic product and how the criteria for a "novel" therapeutic
approach as defined in the second CADET requirement for responsiveness have
been met.

Resource
Sharing Plan: Individuals are required to comply with the
instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model
Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424
(R&R) Application Guide, and should consult with their institution's legal
authorities to define how intellectual property resulting from the research
will be protected.

Appendix: Do not use the Appendix to circumvent page limits. Follow all
instructions for the Appendix as described in the SF424 (R&R) Application
Guide.

Planned Enrollment Report

When conducting clinical research, follow all instructions
for completing Planned Enrollment Reports as described in the SF424 (R&R)
Application Guide.

PHS 398 Cumulative Inclusion Enrollment Report

When conducting clinical research, follow all instructions
for completing Cumulative Inclusion Enrollment Report
as described in the SF424 (R&R) Application Guide.

3. Submission Dates and
Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications
before the due date to ensure they have time to make any application
corrections that might be necessary for successful submission.

Organizations must submit applications to Grants.gov, the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the
status of the application in the eRA Commons, NIH’s electronic system for grants
administration. NIH and Grants.gov systems check the application against many
of the application instructions upon submission. Errors must be corrected and a
changed/corrected application must be submitted to Grants.gov on or before the application
due date. If a Changed/Corrected application is submitted after the deadline,
the application will be considered late.

Applicants
are responsible for viewing their application before the due date in the eRA
Commons to ensure accurate and successful submission.

Information on the submission process and a definition of
on-time submission are provided in the SF424 (R&R) Application Guide.

For assistance with your electronic application or for more information on the electronic submission
process, visit Applying
Electronically.

Important
reminders:All PD(s)/PI(s) must include their eRA Commons ID in the
Credential fieldof the Senior/Key Person Profile Component of the
SF424(R&R) Application Package. Failure to register in the Commons
and to include a valid PD/PI Commons ID in the credential field will prevent
the successful submission of an electronic application to NIH. See Section III of this FOA for information on
registration requirements.

The applicant organization must ensure that the DUNS number it provides on the
application is the same number used in the organization’s profile in the eRA
Commons and for the System for Award Management. Additional information may be
found in the SF424 (R&R) Application Guide.

Upon receipt, applications will be evaluated for
completeness by the Center for Scientific Review and responsiveness by NHLBI.
Applications that are incomplete and/or nonresponsive will not be reviewed.

Post-Submission Materials

Applicants are required to follow the instructions for
post-submission materials, as described in NOT-OD-13-030.

Section V. Application Review Information

1.
Criteria

Only the review criteria described below will be considered
in the review process. As part of the NIH mission,
all applications submitted to the NIH in support of biomedical and behavioral
research are evaluated for scientific and technical merit through the NIH peer
review system.

Overall Impact

Reviewers will provide an overall impact score to reflect
their assessment of the likelihood for the project to exert a sustained,
powerful influence on the research field(s) involved, in consideration of the
following review criteria and additional review criteria (as applicable for the
project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in
the determination of scientific merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature is not
innovative may be essential to advance a field.

Significance

Does the project address an important problem or a
critical barrier to progress in the field? If the aims of the project are
achieved, how will scientific knowledge, technical capability, and/or clinical
practice be improved? How will successful completion of the aims change the
concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field? Does this project define a plan to change
the treatment or approach to management of a disease based on the application
of scientific knowledge?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other
researchers well suited to the project? If Early Stage Investigators or New
Investigators, or in the early stages of independent careers, do they have
appropriate experience and training? If established, have they demonstrated an
ongoing record of accomplishments that have advanced their field(s)? If the
project is collaborative or multi-PD/PI, do the investigators have
complementary and integrated expertise; are their leadership approach,
governance and organizational structure appropriate for the project? Is there
adequate demonstration, particularly in the project timeline, that the
Investigator(s) has a sufficient understanding of the therapeutic development
process to lead the project?

Innovation

Does the application challenge and seek to shift
current research or clinical practice paradigms by utilizing novel theoretical
concepts, approaches or methodologies, instrumentation, or interventions? Are
the concepts, approaches or methodologies, instrumentation, or interventions
novel to one field of research or novel in a broad sense? Is a refinement,
improvement, or new application of theoretical concepts, approaches or
methodologies, instrumentation, or interventions proposed? Does the project
include a novel product or novel approach to management based on disease
biology?

Approach

Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project?
Are potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will the
strategy establish feasibility and will particularly risky aspects be
managed?

If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work
will be done contribute to the probability of success? Are the institutional
support, equipment and other physical resources available to the investigators
adequate for the project proposed? Will the project benefit from unique
features of the scientific environment, subject populations, or collaborative
arrangements?

Additional Review Criteria

As applicable for the project proposed, reviewers will
evaluate the following additional items while determining scientific and
technical merit, and in providing an overall impact score, but will not give
separate scores for these items.

Relevance of Proposed Research to
Regulatory Approval of a Product

Have the investigators demonstrated proficiency in
therapeutic development by defining a progression of research that may
ultimately lead to IND filing? Are the proposed studies likely to be required
for IND application?

Milestones and Timeline

Is there a clear description of the timeline to
enable IND filing, the milestones that need to be achieved for the UH2 and UH3
components of the research, and go/no go decision points in the development
plan?

Protections for Human Subjects

For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or
more of the six categories of research that are exempt under 45 CFR Part 46,
the committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For
additional information on review of the Human Subjects section, please refer to
the Guidelines
for the Review of Human Subjects.

Inclusion of Women, Minorities, and
Children

When the proposed project involves clinical research,
the committee will evaluate the proposed plans for inclusion of minorities and
members of both genders, as well as the inclusion of children. For additional
information on review of the Inclusion section, please refer to the Guidelines
for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live
vertebrate animals as part of the scientific assessment according to the
following five points: 1) proposed use of the animals, and species, strains,
ages, sex, and numbers to be used; 2) justifications for the use of animals and
for the appropriateness of the species and numbers proposed; 3) adequacy of
veterinary care; 4) procedures for limiting discomfort, distress, pain and
injury to that which is unavoidable in the conduct of scientifically sound
research including the use of analgesic, anesthetic, and tranquilizing drugs
and/or comfortable restraining devices; and 5) methods of euthanasia and reason
for selection if not consistent with the AVMA Guidelines on Euthanasia. For
additional information on review of the Vertebrate Animals section, please
refer to the Worksheet
for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures
proposed are potentially hazardous to research personnel and/or the
environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations

As applicable for the project proposed, reviewers will
consider each of the following items, but will not give scores for these items,
and should not consider them in providing an overall impact score.

Applications from Foreign
Organizations

Not Applicable

Select Agent Research

Reviewers will assess the information provided in
this section of the application, including 1) the Select Agent(s) to be used in
the proposed research, 2) the registration status of all entities where Select
Agent(s) will be used, 3) the procedures that will be used to monitor
possession use and transfer of Select Agent(s), and 4) plans for appropriate
biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will consider whether the budget and the
requested period of support are fully justified and reasonable in relation to
the proposed research.

2. Review and Selection
Process

Applications will be evaluated for scientific and technical
merit by (an) appropriate Scientific Review Group(s) convened by the NHLBI,, in
accordance with NIH peer
review policy and procedures, using the stated review
criteria. Assignment to a Scientific Review Group will be shown in the eRA
Commons.

As part of the scientific peer review, all applications:

May undergo a selection process in which only those applications
deemed to have the highest scientific and technical merit (generally the top
half of applications under review) will be discussed and assigned an overall impact
score.

Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted
in response to this FOA.

Applications will be assigned to the appropriate NIH
Institute or Center. Applications will compete for available funds with all
other recommended applications submitted in response to this FOA. Following
initial peer review, recommended applications will receive a second level of
review by the NHLBI Advisory Council. The following will be considered in
making funding decisions:

Scientific and technical merit of the proposed project as
determined by scientific peer review.

Availability of funds.

Relevance of the proposed project to program priorities.

3. Anticipated Announcement
and Award Dates

After the peer review of the application is completed, the
PD/PI will be able to access his or her Summary Statement (written critique)
via the eRA
Commons.

If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH Grants
Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs.

The following special terms of award are in addition to, and
not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB)
administrative guidelines, U.S. Department of Health and Human Services (DHHS)
grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is
applicable when state and local governments are eligible to apply), and other
HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the
cooperative agreement, an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NIH programmatic
involvement with the awardees is anticipated during the performance of the
activities. Under the cooperative agreement, the NIH purpose is to support and
stimulate the recipients' activities by involvement in and otherwise working
jointly with the award recipients in a partnership role; it is not to assume
direction, prime responsibility, or a dominant role in the activities.
Consistent with this concept, the dominant role and prime responsibility
resides with the awardees for the project as a whole, although specific tasks
and activities may be shared among the awardees and the NIH as defined below.

Definitions

External Advisory Board (EAB): The EAB will be composed of
six to ten senior scientists with relevant expertise who are not PDs/PIs of any
of the funded applications in CADET who will assist NHLBI staff in the
oversight of this program. See more about the EAB below under this topic.

Awardee
Rights and Responsibilities

The awardee will have primary responsibility for all aspects of
the proposed research, including any modifications to the product development
plan, selection and conduct of the studies to be performed, the plan for who
will conduct the necessary research, quality control, data analysis and
interpretation, preparation of Regulatory submissions and publications, and
compliance with local IRB requirements.

The awardee must conduct at least 40% of the research in the
therapeutic development plan at the grantee institution(s). This generally
means that at least 40% of the direct costs over the funding period will be
used for research at the investigators' institution(s).

The awardee agrees to address the recommendations from NHLBI
Staff based on assessments of the EAB.

The awardee agrees to accept close coordination, cooperation, and
participation of NIH CADET staff in those aspects of scientific and technical
management of the project as described under "NIH Program Staff
Responsibilities."

The awardee will act as needed to protect intellectual property
that may result from work conducted with support of this grant. Any inventions
which result from CADET funded research will be reported to the Division of
Extramural Inventions & Technology Resources, NIH, within 2 months of the
inventor's initial report to the grantee/contractor organization.

The reporting of inventions will be accomplished electronically
through the NIH Interagency Edison Invention Reporting System.

The awardee will retain custody of and have primary rights to the
data and software developed under these awards, subject to Government rights of
access and requirements for dissemination consistent with current DHHS, PHS,
and NIH policies.

NHLBI
Staff Responsibilities

One NIH Program Staff member will be assigned to each grantee,
but significant decisions will involve a committee of Program Staff members.

The primary assigned NHLBI Program Staff member will be
responsible for the normal scientific and programmatic stewardship of the
award.

NHLBI Program Staff will participate in the continuous monitoring
and coordination of research activities.

NHLBI Program Staff will serve a liaison function for sharing of
information among the awardees with regard to methods, best practices, and
regulatory issues germane to the development of therapeutics for lung diseases.

NHLBI Program Staff will assist the PD(s)/PI(s) in accessing
research resources, especially those needed in response to recommendations from
the External Advisory Board (see below).

NHLBI Program Staff will negotiate milestones with the awardee as
necessary, serving as a liaison between the awardee and appropriate NIH
committees and Institute and Center National Advisory Councils.

The NHLBI reserves the right to withhold funding for the UH3
project if the milestones for the UH2 project have not been successfully
completed..

The NHLBI will constitute an External Advisory Board (EAB) to
ensure routine access to expert advice on issues of drug development for
pulmonary and sleep disorders. NHLBI Program Staff will:

Establish
the charge to the EAB

Convey
materials submitted to the NHLBI by the grantee and establish provisions for
assuring the confidentiality of these materials

Facilitate
discussions on the progress reports submitted by awardees on an annual basis,
the product development plans and milestones submitted by awardees and any
changes to these plans or milestones as requested by the awardee on an annual
basis.

Communicate
recommendations and modifications suggested by the EAB to the awardee for
development plans and milestones, including whether milestones have been
achieved.

The EAB
recommendations will be based on standard requirements for product development
as well as the expected time and resources needed to achieve milestones.

Collaborative
Responsibilities

The awardee and NHLBI staff will work collaboratively to adjust
the research plan and schedule in response to emerging data.

The awardee and NHLBI staff will work cooperatively to coordinate
research activities to be performed through NHLBI programs such as SMARTT,
GTRP, and PACT.

External
Advisory Board Responsibilities

The EAB will assist NHLBI staff in the scientific oversight
of the program and may be asked to:

Discuss the product development plans and milestones submitted by
awardees and any changes to these plans or milestones as requested by the
awardee on an annual basis.

Propose recommended modifications to development plans and
milestones based on standard requirements for product development and expected
time and resources needed to achieve milestones.

Discuss the progress reports submitted by awardees on an annual
basis.

Indicate their assessment of whether agreed milestones have been
successfully met.

Dispute
Resolution:

Any disagreements that may arise in scientific or
programmatic matters (within the scope of the award) between award recipients
and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel
composed of three members will be convened. It will have three members: a
designee of the awardee, one NIH designee, and a third designee with expertise
in the relevant area who is chosen by the other two. This special dispute
resolution procedure does not alter the awardee's right to appeal an adverse
action that is otherwise appealable in accordance with PHS regulation 42 CFR
Part 50, Subpart D and DHHS regulation 45 CFR Part 16. Although a decision to
fund or not to fund the UH3 portion of the study will be based in part on
scientific issues, Dispute Resolution will not be used to resolve disagreements
regarding funding decisions for the UH3 award, since NHLBI retains full
authority for this intrinsically governmental function.

3. Reporting

When multiple years are involved, awardees will be required
to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR)
and financial statements as required in the NIH Grants
Policy Statement.

A final progress report, invention
statement, and the expenditure data portion of the Federal Financial Report are
required for closeout of an award, as described in the NIH Grants
Policy Statement.

The Federal Funding Accountability and Transparency Act of
2006 (Transparency Act), includes a requirement for awardees of Federal grants
to report information about first-tier subawards and executive compensation
under Federal assistance awards issued in FY2011 or later. All awardees of
applicable NIH grants and cooperative agreements are required to report to
the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants
Policy Statement for additional information on this reporting
requirement.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.

Awards are made under the authorization of Sections 301 and
405 of the Public Health Service Act as amended (42 USC 241 and 284) and under
Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.